Antibody-based Protection against Flavivirses

基于抗体的黄病毒保护

• 批准号: 10172827
• 负责人: Michael S Diamond
• 金额: $ 95.33万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172827
• 关键词: Adult; Affect; Amino Acids; Antibodies; Antibody Response; Antigens; Antiviral Therapy; Binding; Biophysics; Complex; Congenital Abnormality; Country; Cryo-electron tomography; Cryoelectron Microscopy; Dengue Fever; Dengue Hemorrhagic Fever; Dengue Infection; Dengue Vaccine; Dengue Virus; Dengvaxia; Development; Diagnosis; Diagnostic; Diagnostic Reagent; Diamond; E protein; Encapsulated; Engineering; Epitopes; Exposure to; Fetus; Flavivirus; Generations; Genes; Goals; Guillain Barré Syndrome; Human; Immune; Immunization; Immunize; Individual; Infection; Laboratories; Life; Link; Mediating; Messenger RNA; Microcephaly; Modeling; Molecular Conformation; Monitor; Monoclonal Antibodies; Mus; Mutagenesis; Mutate; Mutation; Paper; Pathogenesis; Pathogenicity; Pregnancy; Publishing; Role; Sampling; Serology; Serotyping; Shock; Spontaneous abortion; Structural Protein; Structure; Syndrome; Temperature; Therapeutic antibodies; Translating; Vaccination; Vaccines; Variant; Viral; Virion; Virus; Zika Virus; Zika virus vaccine; atomic interactions; base; biophysical techniques; cross reactivity; genetic variant; human monoclonal antibodies; immunogenicity; improved; in vivo; insight; lipid nanoparticle; multiple myeloma M Protein; mutant; neutralizing antibody; novel; particle; polyclonal antibody; response; vaccine candidate; vaccine development; vaccine-induced antibodies; virus genetics

PROJET SUMMARY/ABSTRACT Globally, the four serotypes of DENV cause an estimated 390 million new cases of dengue fever and 500,000 cases of dengue hemorrhagic fever (DHF) per year. Zika virus (ZIKV) is a related emerging virus linked to Guillain-Barre syndrome in adults, and microcephaly, congenital malformations, and spontaneous abortion of the fetus during pregnancy. Currently, no antiviral therapy is available for either virus. In the first two cycles of this collaborative and inter-disciplinary R01, we developed panels of monoclonal antibodies (Abs) against the E proteins of all four DENV serotypes and analyzed their structural, biophysical, and cellular mechanisms of neutralization. These studies defined novel epitopes on DENV E proteins recognized by inhibitory Abs, some of which are not solvent-accessible according to existing atomic models of the virus particle. We also defined the dynamic state of DENV and related flaviviruses, determined the atomic structure of mature and immature ZIKV, characterized atomic interactions between DENV and ZIKV virions, E protein, and new highly neutralizing mouse and human Abs, and identified how different maturation states influence epitope accessibility and Ab neutralization. Our studies revealed that flavivirus structure is more complex than anticipated and is likely a heterogeneous and dynamic ensemble of different states, each of which may interact differentially with Abs. In this renewal, our collaborative and inter-disciplinary team hopes to gain insight into questions about the antigenicity of flavivirus virions and subviral particles (SVPs) as well as the cross-reactivity that limits vaccine and diagnostic development and may affect pathogenesis. Our group will define new states of DENV and ZIKV particle structure and determine how these states influence epitope exposure and interaction with specific neutralizing Abs available in our laboratories. We also will compare the atomic structure of SVPs with infectious virions, determine how these differences affect binding and induction of neutralization Abs, and characterize further the structural basis of cross-reactivity of DENV and ZIKV. Our studies may facilitate the generation of novel antigens and immunogens with improved capacity to detect and elicit specific protective Ab responses against DENV, ZIKV, and likely other emerging flaviviruses.

Projet摘要/摘要 在全球范围内，DENV的四种血清型导致估计3.9亿例登革热病例和50万例 登革热出血热（DHF）病例。 Zika病毒（ZIKV）是一种相关的新兴病毒 成年人的Guillain-Barre综合征，小头畸形，先天性畸形和自发流产 怀孕期间的胎儿。目前，任何一种病毒都无法使用抗病毒疗法。在前两个循环中 这种协作和跨学科的R01，我们开发了针对E的单克隆抗体（ABS）面板 所有四种DENV血清型的蛋白质，并分析了它们的结构，生物物理和细胞机制 中和。这些研究定义了关于通过抑制性ABS识别的DENV E蛋白的新表位，有些 根据病毒颗粒的现有原子模型，其溶剂不可访问。我们也定义了 DENV和相关黄病毒的动态状态确定了成熟和不成熟的原子结构 ZIKV，表征DENV和ZIKV病毒体之间的原子相互作用，E蛋白质和新的高度 中和小鼠和人类ABS，并确定不同的成熟状态如何影响表位 可访问性和AB中和。我们的研究表明，黄病毒结构比 预期的，可能是不同状态的异构和动态的合奏，每个国家都可能相互作用 用ABS差异。在此续约中，我们的合作和跨学科团队希望深入了解 关于黄病毒病毒体和病毒颗粒（SVP）的抗原性问题以及交叉反应性 这限制了疫苗和诊断发育，可能会影响发病机理。我们的小组将定义新州 DENV和ZIKV粒子结构的结构，并确定这些状态如何影响表位的暴露和 与我们实验室中可用的特定中和腹肌相互作用。我们还将比较原子 具有传染性病毒体的SVP的结构，确定这些差异如何影响结合和诱导 中和ABS，并进一步表征DENV和ZIKV交叉反应性的结构基础。我们的 研究可能会促进新型抗原和免疫原子的产生，并提高检测能力的能力和 引起针对DENV，ZIKV以及可能其他新兴的黄病毒的特定保护AB反应。